The overall goal of the proposed study is to examine the consequences of adolescent alcohol exposure on frontal brain function, while controlling for pre-existing genetic and environmental background factors. We hypothesize that prefrontally mediated executive and cognitive control functions can be particularly vulnerable to alcohol effects due to their continuing development during adolescence. Animal studies suggest that adolescent exposure to alcohol can produce long-lasting impact on the brain and behavior, however, human studies are very scarce and have been largely limited to a case-control design that precludes the discrimination between the consequences of alcohol use and pre-existing vulnerability factors predating the onset of drinking. The proposed study will address this fundamental limitation by implementing a co-twin control design based on the comparison of twins concordant or discordant for alcohol exposure during adolescence. Specific aims of the study are: 1) to examine associations between adolescent alcohol exposure and neurocognitive functioning and to determine the extent to which these associations depend on the age of onset of alcohol use, the extent of exposure, and recency of alcohol use, 2) to isolate consequences of alcohol exposure from pre-existing deficits using the co-twin control approach, and 3) to examine the role of biologically relevant genetic polymorphisms in individual susceptibility to deleterious effects of alcohol exposure on neurocognitive functioning (gene by exposure interaction). These aims will be achieved through an interdisciplinary study integrating cognitive neuroscience, co-twin control, and pharmacogenetic approaches and using a hypothesis-driven selection of dependent measures that have been linked to specific regions of the prefrontal cortex in previous studies and tap into specific aspects of executive functioning including action monitoring, response inhibition, reward and punishment processing, decision making, and executive attention. The study sample will include 280 twins (age 18-22) with varying degree of alcohol exposure. The sample will be drawn from ongoing epidemiological twin studies of the applicant and co-investigators, with selection of twin pairs based on already available data on the history of alcohol and tobacco use. The proposed study should increase our understanding of long-term consequences of underage drinking for neural and cognitive processes relevant to addiction vulnerability. Alcohol use, including heavy drinking episodes, continues to be common among adolescents and. Animal and human research suggests that alcohol exposure during adolescence can interfere with normal brain development and affect cognitive function and behavior later in life. However, little is still known about the effects of alcohol on neural mechanisms that underlie higher cognitive functions such as self-control and decision making in humans. By addressing this important issue, this study will increase our understanding of long-term cognitive and behavioral consequences of underage drinking and their neurobiological basis. The knowledge gained in the study can be used for the development of better prevention and intervention strategies aimed at underage drinking. [unreadable] [unreadable] [unreadable]